2.1 Study design and patient selection

The ISAR-DESIRE registry is an observational study of patients who underwent PCI for the treatment of ISR between January 2007 and February 2021 at the Deutsches Herzzentrum München, Munich, Germany and the 1. Med. Klinik, Klinikum rechts der Isar, Technical University, Munich, Germany. The present analysis focuses on ISR located in SVG.

2.2 Interventional procedure and medications

PCI of ISR was performed according to standard clinical practice. All patients were treated with either balloon angioplasty (BA) including DCB or implantation of DES. Patients treated with both, DES and BA, for the same ISR lesion were assigned to the DES group. The decision regarding the individual therapy strategy was determined by the treating physician. According to local standards, predilatation was recommended for all patients undergoing PCI for ISR, the use of scoring or debulking devices was left to the operators' discretion, as well as the decision to perform postdilatation after stenting. During the procedure, patients usually received 500 mg aspirin intravenously and body weight adjusted intraarterial or intravenous heparin or bivalirudin immediately after the decision to perform the intervention. After the intervention all patients received aspirin indefinitely and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) according to clinical presentation and recommendations at the time of PCI.

2.3 Data collection and quantitative coronary angiography analysis

Personnel of the clinical data management center (ISAResearch-Center) collected relevant data on source-documented hospital chart reviews. This data included information regarding clinical and lesion-related parameters at the time of initial and repetitive PCI for first and recurrent ISR. The required data for this study was entered into an anonymized study database. Angiographic and procedural parameters of interest included the type of intervention (BA vs. DES), balloon diameter and maximum balloon pressure, total stented length, and stent diameter as well as TIMI grade flow pre and post PCI.

2.4 Endpoints

Endpoints of interest regarding this analysis were survival after first PCI due to ISR in SVG, time to ISR recurrence, target lesion revascularization (TLR), target vessel myocardial infarction (TVMI), nontarget vessel revascularization (NTVR), nontarget vessel myocardial infarction (NTVMI), and stent thrombosis (ST). Target vessel revascularization (TVR) was defined as revascularization in the target vessel outside the target lesion. Event rates are presented as Kaplan–Meier 10-year event rates for all-cause mortality and cumulative 10-year incidences after accounting for the competing risk of death for the other endpoints. The definition of myocardial infarction (MI) used in this analysis was based on the Third Universal Definition of Myocardial Infarction.¹⁸ The definitions of ISR, ST, TLR, and NTVR used in this trial were adapted from the Academic Research Consortium.^{19, 20}

2.5 Statistics

Baseline descriptive parameters are presented as mean ± standard deviation for continuous data and numbers with percentages for categorical data. Survival analyses were performed according to Kaplan–Meier method and the treatment of the first ISR was defined as time zero. Univariate analysis considering clinical and lesion-related variables was performed. Unadjusted hazard ratios and 95% confidence intervals were calculated with the use of Cox proportional models. We applied a multivariable linear model to identify the independent predictors of the total number of repeat TLR per patient. A 2-tailed p < 0.05 was considered statistically significant. Statistical software R (Version 4.0, R Foundation for Statistical Computing) was used for all analyses.

3.1 Baseline and procedural characteristics

A total of 163 patients underwent PCI due to ISR located in SVG. The mean age of this patient cohort was 72.6 ± 8.6 years and 90.8% were male. 36.8% suffered from diabetes, 98.2% from arterial hypertension and 84.7% from hypercholesterolemia. Nearly all patients (99.4%) presented with coronary multivessel disease and 58.9% had history of myocardial infarction. Most patients were admitted due to stable coronary artery disease (57.7%). Further clinical baseline characteristics are presented in Table 1.

A total of 186 ISR lesions located in SVG were treated. ISR were treated with DES-implantation in 64.0% and with BA in 36.0%. In the BA group 35.8% (24/67 patients) were treated with a DCB. In the total cohort, median maximum balloon diameter was 3.5 mm (3.0 mm; 4.0 mm), median maximum balloon pressure was 16.0 atm (13.0; 18.0), median stented length was 25.0 mm (18.0; 38.0 mm) and median stent diameter was 3.5 mm (3.0 mm; 4.0 mm). Postinterventional 93.0% had TIMI grade flow 3. A summary of procedure-related characteristics is shown in Table 2.

3.2 Clinical outcomes

The median follow-up duration was 5.1 years (75% CI 2.8; 8.5). Ten-year all-cause mortality rate after PCI of ISR in SVG was 58.2%, TVMI rate was 15.4% and TLR rate was 22.6% after 10 years (Figure 1). A total of 15.3% underwent TVR, 51.3% underwent NTVR and in 11.1% NTVMI occurred after 10 years. One ST was detected. An overview of the clinical outcomes is presented in Table 3. Outcomes according to the type of treatment (DES vs. BA) did not differ statistically significant: the 10-year rate for all-cause mortality was 55.7% versus 63.2% (p = 0.181), for TVMI 13.8% versus 18.6% (p = 0.215) and for TLR 21.8% versus 25.0% (p = 0.764) (Figure 2). The rates for NTVR (56.2% vs. 40.7%, p = 0.205), NTVMI (12.3% vs. 8.5%, p = 0.709), TVR (12.4% vs. 21.1%, p = 0.088) and ST (1.4% vs. 0.0%, p = 0.468) were comparable as well. Moreover, BA treated patients have been divided in DCB treated and plain old balloon angioplasty (POBA) treated patients based on an exploratory analysis to further illustrate clinical outcomes.

3.3 Predictors of TLR

In total, there were 332 repeat TLR, or 2.04 ± 1.78 repeat TLR per patients. In the multivariable model, the number of repeat TLR inversely correlated with patient's age (p = 0.034) (Table 4).

3.4 Recurrent ISR

A total of 70 lesions (37.6%) were treated due to recurrent ISR at least twice, 30 lesions were treated with a third PCI, 21 lesions underwent a fourth PCI and 24 lesions underwent more than four PCIs. Median elapsed time between PCI of first SVG ISR and PCI of second SVG ISR was 348.4 days (Q1 198.3; Q3 729.8), between second and third PCI 203.1 days (Q1 195.3; Q3 642.9), between third and fourth PCI 315.3 days (Q1 159.0; Q3 528.4) and between later following PCIs it was 186.0 days (Q1 85.1; Q3 337.7). Median time between first and recurrent ISR was 270.8 days. The rates of DES-implantation for the second, third, fourth and later recurrent ISR were 57.7%, 43.3%, 52.4%, and 41.7%, respectively. Recurrent ISR were treated with DES in a comparable proportion as during first ISR (p = 0.075). Overall, a total of 129 patients had an angiographic follow-up (median time after last PCI of SVG-ISR: 682 days) and the rate of occluded SVGs was 15.5%.

4.1 Limitations

The results of our analysis should be interpreted with caution as there are several limitations. First, it is an observational retrospective study and so subject to all limitations of this design. Thus, some information is not available for every patient, for example, exact cause of death or selected procedural characteristics of patients who were initially treated elsewhere. Furthermore, the median follow-up duration was 5.1 years (75% CI 2.8; 8.5). Because the study period in the underlying trial extended to 2021, only 67 of the patients who survived up to the last contact date were eligible for a 5-year follow-up. Nine of these 67 patients (13.6%) had incomplete 5-year follow-up. Second, the choice of PCI in case of SVG ISR was left to the operator's discretion and thus, a selection bias cannot be ruled out. Moreover, information regarding the decision making whether to treat the native vessel or the SVG are not available, especially in the case of recurrent ISR. Third, substantial advances in interventional treatment and antithrombotic therapy were made during the inclusion period. This may be a reason why DCB was used only in the minority of the patients. In addition, intravascular imaging has not been systematically applied. Fourth, the number of included patients with SVG ISR is small and the occurrence of rare events such as ST might be underreported. Fifth, the present analysis just considered DES-ISR in SVG and did not deal with DES-ISR in arterial bypass grafts. However, a minority of just approximately 2.5% of PCI in patients with prior CABG refers to arterial bypass grafts.²³ Finally, there were numerically differences in DES- and BA-treated patients for several clinical outcomes such that even larger series need to be analyzed before firm conclusions can be made on the success rates of the two different treatment modalities.